PROJECT SUMMARY Skin cancer, already the most common cancer in the U.S., is increasing dramatically in incidence due to the combined effects recreational sun exposure and the aging of the U.S. population. This proposal will apply powerful genome-wide epigenetic techniques to human patient samples and in vitro and in vivo models to determine how alterations in the skin epigenome drive cutaneous carcinogenesis, and identify chromatin modifiers that may be targeted for prevention and treatment. By focusing on the role of epigenomic dysregulation in the promotion of keratinocyte cancers, this project directly engages the Keratinocyte Biology and Diseases Program at NIAMS, and specifically addresses the goals of the NIAMS 2015-2019 Long-Range Plan, including the investigation of chromatin structure and epigenetic mechanisms in the skin. Candidate: Brian Capell received his M.D. and Ph.D. from New York University in 2009. In 2013, he was board-certified following the completion the Dermatology Residency Program at the University of Pennsylvania. He is currently an Instructor and Postdoctoral Fellow in the Dermatology Department and Epigenetics Program at Penn, pursuing training in a laboratory dedicated to understanding epigenetic mechanisms involved in cancer and aging. This proposal builds upon his established interest in cellular senescence and genetics, will produce novel scientific results, and additionally provide critical training to the candidate. The applicant's long-term goal is to become a R01-funded independent investigator studying how epigenetic mechanisms contribute to skin diseases. Environment: Dr. Capell's mentor, Dr. Shelley Berger, provides unparalleled expertise. Dr. Berger is world-renowned for her research on epigenetics and chromatin structure and function in genomic regulation. She has been continuously funded by NIH throughout her career and offers extensive resources for the work described in this proposal. Dr. Berger also has a robust track record of mentorship. The applicant's career development plan entails rigorous training in epigenetic techniques and computational biology, including coursework in these areas crucial to his success, and close guidance from a diverse and dedicated network of scientific advisors. In addition, Dr. Capell has the full support of the Department of Dermatology at Penn. Research: Dr. Capell's preliminary results show that inflammation during cellular senescence, known as the senescence-associated secretory phenotype (SASP), can be attenuated by novel epigenetic drugs. This occurs through abrogation of DNA damage response activation and direct modification of the local chromatin environment over SASP genes. How the epigenome may be altered and drive skin carcinogenesis is poorly understood. As recent studies have demonstrated that genetic mutations alone are insufficient for the development of skin cancer, the investigators hypothesize that an understanding of epigenetic processes during the earliest stages of skin carcinogenesis may provide novel opportunities for prevention and therapy. This proposal will build on Dr. Capell's preliminary data to 1) define the global epigenomic and transcriptional alterations that occur during skin photoaging and carcinogenesis, and 2) identify chromatin regulators that can be targeted to prevent UV-induced epigenomic alterations and carcinogenic transformation. The proposed scientific inquiry, Dr. Berger's mentorship, and the enthusiastic support of the candidate's Department and advisory committee will enable Dr. Capell to launch a successful career as an independent physician-scientist.